CUG repeat expansion RNA (r(CUG)exp)

CUG repeat expansion RNA is a pathogenic, non-coding or untranslated RNA molecule characterized by an abnormally high number of CUG trinucleotide repeats. In diseases like myotonic dystrophy type 1 (DM1), these expansions occur in the 3' untranslated region (UTR) of the DMPK gene, where they fold into stable hairpin structures. These structures act as toxic 'molecular sinks' that sequester vital RNA-binding proteins, most notably the Muscleblind-like (MBNL) family, while inducing the upregulation of others like CELF1. This sequestration leads to widespread alternative splicing defects, known as a 'splicopathy,' which results in multi-systemic symptoms including myotonia, muscle wasting, and cardiac conduction issues. Therapeutic strategies focus on either degrading the toxic RNA using antisense oligonucleotides (ASOs), blocking protein-RNA interactions with small molecules, or using CRISPR-based tools to remove the expansions. Selectivity is a major challenge, as therapies must distinguish between the long, pathogenic expansions and the short, functional CUG repeats found in various healthy transcripts throughout the genome.

Other names

Toxic CUG repeat RNAExpanded CUG repeat RNACUGexp RNADMPK expanded repeat RNAr(CUG)exp

Therapeutic agents target CUG repeat expansion RNA through several mechanisms: inducing RNase H-mediated degradation of the transcript (antisense oligonucleotides), binding the RNA hairpin structure to displace sequestered MBNL proteins (small molecule binders), or utilizing selective RNA-cleaving agents (e.g., Cugamycin). Other approaches include inhibiting the transcription of the expanded repeats or stimulating the nuclear exosome complex to degrade toxic transcripts particularly when they are located within introns.